1: J Neuroinflammation. 2008 May 21;5:19.

Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct
rodent models of Parkinson's disease.

Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS.

Department of Pharmacology, The School of Pharmacy, 29-39 Brunswick Square,
London WC1N 1AX, UK. alexander.harkavyi@pharmacy.ac.uk

BACKGROUND: It has recently become apparent that neuroinflammation may play a
significant role in Parkinson's disease (PD). This is also the case in animal
paradigms of the disease. The potential neuroprotective action of the
glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is
protective against cytokine mediated apoptosis and may stimulate neurogenesis,
was investigated In paradigms of PD. METHODS: Two rodent 'models' of PD,
6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the
effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide
range of behavioural, neurochemical and histological tests to measure integrity
of the nigrostriatal system. RESULTS: EX-4 (0.1 and 0.5 mug/kg) was given seven
days after intracerebral toxin injection. Seven days later circling behaviour was
measured following apomorphine challenge. Circling was significantly lower in
rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle.
Consistent with these observations, striatal tissue DA concentrations were
markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle
groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly
reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in
rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS
+ vehicle treated animals was markedly lower than in sham-operated or EX-4
treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the
striata of toxin lesioned freely moving rats. CONCLUSION: The apparent ability of
EX-4 to arrest progression of, or even reverse nigral lesions once established,
suggests that pharmacological manipulation of the GLP-1 receptor system could
have substantial therapeutic utility in PD. Critically, in contrast to other
peptide agents that have been demonstrated to possess neuroprotective properties
in pre-clinical models of PD, EX-4 is in current clinical use in the management
of type-II diabetes and freely crosses the blood brain barrier; hence, assessment
of the clinical efficacy of EX-4 in patients with PD could be pursued without
delay.

PMCID: PMC2426681
PMID: 18492290 [PubMed - indexed for MEDLINE]